Anabolic treatments that restore bone health improve clinical outcomes in dentistry and medicine. Parathyroid hormone (PTH) has significant anabolic effects on bone metabolism. However, the molecular mediators of PTH's anabolic effects remain unclear. Our research focuses on PTH-induced primary genes that act as transcription factors to target late gene expression and propagate changes in osteoblastic function. We have identified NGFI-B nuclear orphan receptors (Nurr1, Nur77, NOR-1) as PTH-induced primary genes in osteoblasts. NGFI-B proteins regulate transcription and cellular differentiation through NGFI-B response elements (NBREs) in target gene promoters. Nurr1 protein transactivated the rat osteocalcin promoter through a wild type (WT), but not mutant (mut), NBRE. PTH induced the PPARgamma coactivator PGC-1alpha. PGC-1alpha, in turn, strongly enhanced Nurr1-induced transactivation of the WT, but no mut, OCN promoter, suggesting that Nurr1 binding to the NBRE is critical in transcriptosome assembly on NGFI-B target promoters. We observed that the consensus PPARgamma response element (PPRE) contains an NBRE. Indeed, recombinant and PTH-induced Nurr1 protein bound to a consensus PPRE. Intriguingly, in addition to synergizing with PGC1alpha, Nurr1 and Nur77 also heterodimerize with PPARgamma's obligatory partner, RXR. These data suggest that NGFI-B and PPARgamma, signaling may converge on PPRE-containing promoters. We propose that NGFI-B proteins downregulate PPARgamma-responsive genes thereby promoting osteogenesis over adipogenesis. To that effect, PTH inhibited the PPARg, target gene CD36 in primary osteoblasts. We hypothesize that NGFI-B genes are critical mediators of osteoblast differentiation and function through target promoter regulation and selective cofactor recruitment.
Our Specific Aims are to: 1) study transcription regulation by NGFI-B nuclear orphan receptors in osteoblasts, 2) examine PTH-induction of and NGFI-B interactions with PGC-1alpha, 3) investigate the effect of targeted NGFI-B overexpression on bone in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
2R01DE013316-06
Application #
6823824
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Shum, Lillian
Project Start
1999-08-01
Project End
2009-05-31
Budget Start
2004-08-01
Budget End
2005-05-31
Support Year
6
Fiscal Year
2004
Total Cost
$372,238
Indirect Cost
Name
University of California Los Angeles
Department
Dentistry
Type
Schools of Dentistry
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Magyar, Clara E; Aghaloo, Tara L; Atti, Elisa et al. (2008) Ostene, a new alkylene oxide copolymer bone hemostatic material, does not inhibit bone healing. Neurosurgery 63:373-8;discussion 378
Pirih, Flavia Q; Abayahoudian, Rosette; Elashoff, David et al. (2008) Nuclear receptor profile in calvarial bone cells undergoing osteogenic versus adipogenic differentiation. J Cell Biochem 105:1316-26
Aghaloo, Tara L; Amantea, Christopher M; Cowan, Catherine M et al. (2007) Oxysterols enhance osteoblast differentiation in vitro and bone healing in vivo. J Orthop Res 25:1488-97
Nervina, Jeanne M; Magyar, Clara E; Pirih, Flavia Q et al. (2006) PGC-1alpha is induced by parathyroid hormone and coactivates Nurr1-mediated promoter activity in osteoblasts. Bone 39:1018-25
Ozkurt, Ibrahim C; Pirih, Flavia Q; Tetradis, Sotirios (2004) Parathyroid hormone induces E4bp4 messenger ribonucleic acid expression primarily through cyclic adenosine 3',5'-monophosphate signaling in osteoblasts. Endocrinology 145:3696-703
Pirih, Flavia Q; Tang, Alan; Ozkurt, Ibrahim C et al. (2004) Nuclear orphan receptor Nurr1 directly transactivates the osteocalcin gene in osteoblasts. J Biol Chem 279:53167-74
Ozkurt, Ibrahim C; Tetradis, Sotirios (2003) Parathyroid hormone-induced E4BP4/NFIL3 down-regulates transcription in osteoblasts. J Biol Chem 278:26803-9
Pirih, Flavia Q; Nervina, Jeanne M; Pham, Lee et al. (2003) Parathyroid hormone induces the nuclear orphan receptor NOR-1 in osteoblasts. Biochem Biophys Res Commun 306:144-50
Tsingotjidou, A; Nervina, J M; Pham, L et al. (2002) Parathyroid hormone induces RGS-2 expression by a cyclic adenosine 3',5'-monophosphate-mediated pathway in primary neonatal murine osteoblasts. Bone 30:677-84
Tetradis, S; Bezouglaia, O; Tsingotjidou, A et al. (2001) Regulation of the nuclear orphan receptor Nur77 in bone by parathyroid hormone. Biochem Biophys Res Commun 281:913-6

Showing the most recent 10 out of 11 publications